Antiproteases are increased in bronchoalveolar Y. Sibille•t.

Eur Respir J
1988, 1, 496-504
Antiproteases are increased in bronchoalveolar
lavage in interstitial lung disease
Y. Sibille•t. J.B. Martinof, P. Staquet", L. Delaunois·, B. Chatelain**, D.L. Delacroixt
Antiproteases are increased in hronchoalveolar lavage in interstitial lung
disease. Y. Sibille, J.B. Martinot. P. Staquet, D. Delaunois, B. Chatelain,
D.L. Delacroix.
ABSTRACT: The present study evaluates different cellular and soluble
components in the bronchoalveolar lavage (BAL) from patients with interstitial
lung disease. We observed an increased T 4 /T8 Jymphocyte ratio in BAL but not
in blood from 24 patients with active pulmonary sarcoidosis compared to sixteen
normal individuals and to eleven patients with inactive pulmonary sarcoidosis.
Seven patients with hypersensitivity pneumonitis had a normal T 4 /T 8 ratio. In
the active sarcoidosis and hypersensitivity pneumonitis groups, a 1-Protease
Inhibitor (a 1 PI) in BAL is significantly higher than in the normal group and a
significant correlation between the two antiproteases (a 2 -macroglobulin and
a 1 PI) is observed. These data demonstrate that antiprotease levels (a 1 PI and
a 2 M) are increased in the lower respiratory tract of patients with interstitial
lung disease and that among cellular and soluble components of BAL, a 2 M
represents a sensitive marker of the alveolitis.
Eur Respir J. 1988. I, 498-504.
The interstitial lung diseases include disorders of
unknown and known aetiology, and even distinguishing among the diseases of known cause is sometimes
tedious. In addition to the problem of diagnosing
specific causes of interstitial lung disease, the assessment of disease activity, especially in pulmonary
sarcoidosis, remains an important issue. In recent
years three techniques have been proposed to assess
disease activity in sarcoidosis: 67Gallium scan, Angiotensin Converting Enzyme (ACE) and Bronchoalveolar Lavage (BAL) [1-4). In the past ten years
BAL has been widely used and may be a useful
technique in the management of interstitial lung
diseases {5, 6]. The lymphocytosis of the BAL has
been proposed as an index of disease activity in
pulmonary sarcoidosis: a high percentage of lymphocytes in the BAL corresponding to a 'high intensity
alveolitis' [7, 8]. Furthermore, the pre-treatment BAL
lymphocytosis was recently reported to predict steroid responsiveness in sarcoidosis [9].
Other groups have, however, failed to demonstrate
a correlation between BAL lymphocytosis and disease
activity and consider an increased T helper/T suppressor ratio (T 4 /T 8 ) in the BAL as a better index for
active disease [10, 11]. This BAL T 4 /T8 has also been
shown to drop to normal values with regression of the
disease. In contrast with these cellular studies, the
usefulness of soluble components in BAL has not yet
been demonstrated [6].
We recently reported that BAL <l 2 -macroglobulin
(<l 2 M) is increased in BAL from patients with active
interstitial lung diseases [12]. These studies confirm
and extend our previous observations and include
• Pulmonary Section and
•• Haematology Laboratory. University Hospital of Mont-Godinne, Belgium.
t Experimental Medicine Unit, Institute of
Cellular and Molecular Pathology, Catholic
University of Louvain, Belgium.
Correspondence: Y. Sibille, Cliniques UCL
Mont·Godinne, B-5180 Yvoir, Belgium.
Keywords: Antiproteases; BAL; interstitial
lung disease.
Received: July 15, 1987; accepted after revision
August 8, 1987.
data for <l 1 -protease inhibitor (<l 1 PI) which is the
predominant antiprotease in the serum, whose fate in
interstitial lung disease has not yet been explored. The
purpose of this study is to evaluate in BAL different
cellular parameters (including lymphocyte subpopulations) and soluble components (including the two
major antiproteases <l 1PI and <l2 M) during the course
of interstitial lung disease.
Material and methods
Study popu/ations
l. Single lavage group. After agreement of the local
Ethics Committee, the following non-smoking individuals were investigated: 16 normal volunteers
(group I) and 35 consecutive patients with biopsy
proven sarcoidosis (22 newly diagnosed and 13 with
disease known for l - 5 years before referral to us)
further subdivided into group II and group III.
Group II consisted of 24 untreated patients defined as
'active' sarcoidosis based on BAL lymphocytosis
> 15%. These included 10 patients with radiological
stage I (hilar adenopathy), 7 with stage 11 (hilar
adenopathy and lung infiltrates) and 7 with stage Ill
(lung infiltrates alone). Group III included 11 patients
with pulmonary sarcoidosis considered as 'inactive'
based on BAL lymphocytosis < 15% (3 stage I, 3
stage n, 5 stage Ill) including 3 patients treated with
steroids. Group TV consisted of 7 untreated patients
with typical hypersensitivity pneumonitis. Three
patients were pigeon breeders, two fancy bird breeders and two had farmer's lung.
2. Serial /avages group. Twelve patients with
499
ANTIPROTEASES IN BRONCHOALVEOLAR LAVAGE
pulmonary sarcoidosis were sequentially lavaged
(one, two or three times) after the initial BAL. This
group included two patients under steroid treatment
at the time they were referred to us.
Bronchoalveolar lavage
Bronchoalveolar lavage was performed as described
[5, 12, 13] through the fibre-optic bronchoscope using
200 ml sterile 0.9% saline solution in 50 ml aliquots
instilled and gently aspirated. The first aliquot
(bronchial lavage) was discarded and the studies were
performed on the three following aliquots. The
recovered fluid was filtered through a single layer of
gauze to remove gross mucus and an aliquot was saved
for a total cell count, using a CoulterR cell counter, and
for cell differential. The lavage was then centrifuged
and the cell pellet was used in lymphocyte subpopulation studies, while the superoatant was kept at
- 20°C for protein analysis.
Cellular studies
Cell differentials were performed on cytospin
preparations, using the same cytocentrifuge (Cytospin
I) at the same centrifuge speed to minimize artificial
variations between the different samples [14]. Lymphocyte subpopulations in blood (obtained on the
day of the lavage) and BAL were determined using
the fluorescent monoclonal antibodies OKT 11 (T
lymphocytes), OKT4 (helper) and OKT8 (suppressor)
according to R EINHERZ et al. [15]. The cell bound
fluorescence in the lymphocyte population was determined using an EPICS C CoulterR flow cytometer.
Data are expressed as percentage of positive (OKT 11 ,
OKT4 , OKT8 ) cells in the total lymphocyte population.
Proteins assays
Serum levels of albumin, IgG, IgM and cx 1 PI were
determined by immunonephelometry [16]. The immunoradiometric assay (IRMA) was used for measure-
ment of cx 2 M in the serum and for all proteins in BAL.
This assay, previously described in detail [12, 17],
does not require concentration of the BAL fluid.
Results are expressed as previously in coefficient of
excretion relative to albumin (RCE), to correct for
both serum concentration of the different proteins
and variable dilution of BAL (12].
RCE= BAL protei~
serum protem
I
BAL albumin
serum albumin
Statistical analysis
Values in the different groups were tested for
significance using an unpaired t-test and correlations
between variables were evaluated by linear regression.
Results
Cell differentials and lymphocyte subpopulations
BAL volumes recovered, total cell counts and cell
differentials in each group are given in table I. The
lavage fluid from patients with active sarcoidosis and
hypersensitivity pneumonitis contained more cells
than the BAL from normal individuals and from
patients with inactive sarcoidosis. Patients with active
sarcoidosis also demonstrated a significantly higher
percentage of lymphocytes than normals and patients
with inactive sarcoidosis. Patients with hypersensitivity pneumonitis had higher percentages of both
lymphocytes and polymorphonuclear neutrophils.
As illustrated in figure I , the group of patients with
active sarcoidosis had a significantly higher T 4 /T 8
ratio in the BAL than the normal group or the groups
of patients with inactive sarcoidosis or hypersensitivity pneumonitis. This increased T 4 /T 8 ratio in the
BAL from the active sarcoidosis group reflects a
combined increase of BAL T 4 subpopulations and a
decrease of BAL T 8 subpopulations. No significant
difference was observed in the blood T 4 /T 8 ratio
between the different groups (data not shown).
Table 1. - Cellular components of BAL
BAL
recovery
ml
Normals
n=l6
Sarcoidosis
n=35
Active sarcoidosis
n=24
Inactive sarcoidosis
n=ll
Hypersensitivity
pneumonitis n= 7
Cell count
xlQ4/ml BAL
% macrophages
% lymphocytes
%PMN
%eosinophils
160.9±19.) •
17.2±5.8
91.1± 8.4
8.2± 8.0
0.5±0.7
0.06±0.2
136.3±28.2
28.1±13.8*
76.4± 8.1*
22.6±12.8*
0.8±0.8
0.1 ±0.4
133.6±30.7
30.9±12.9*
69.8±10.2*
29.3± 9.9*
0.6±0.8
0.2 ±0.4
141.3±23.0
23.6±15.6
89.3± 3.8
9.7± 3.3
1.1±1.0
0
136.0±19.7
66.8±25.2*
38.7±20.7*
39.5±28.7*
6.5±5.6*
1.3 ±1.2*
+Mean±sD. *p<0.05 when compared to normal group values. PMN: polymorphonuclear neutrophils
500
Y. SIB IL LE ET AL .
Table 2. - BAL immunoglobulins G and M (in RCE)
lgG
IgM
Nonnals
n=l6
Active sarcoidosis
n=24
Inactive sarcoidosis
n=ll
Hypersensitivity pneumonitis
n=7
0.74±0.26+
(0.20-1.38)0
0.08±0.07
(0.01--0.16)
1.90±0.90**
(0.64-3.62)
0.51±0.43**
(0.08-1.65)
1.08±0.50*
(0.60-1.80)
0.28±0.20*
(0.12--0.49)
2.28±1 .02*
(1.42-4.00)
1.54±1.21 **
(0.40-4.75)
•mean±sn. 0 range in brackets, *p<0.05, **p<O.Ol when compared to nonnals, p<0.05 when compared to inactive sarcoidosis;
RCE: relative coefficient of excretion.
• (30.3)
• (23 .2)
•(18.2}
-;:::;
•
1.4
•
1.3
14
1.2
13
•
1.1
12
1.0
•
11
0.9
10
0.8
•
9
•
•
0.7
•
8
7
•
•
•
0.5
•
6
0.4
5
0.3
4
0.2
3
·~
rlt-
2
...
0.6
I•
a.
•
0
N
•
0.1
0
N
SA
SNA
HP
Fig. I. The T 4 /T 8 lymphocyte ratio in BAL from active
sarcoidosis patients (SA) (n = 24) is significantly increased when
compared to norma Is (N) (n = 16) and non-active sarcoidosis
patients (SNA) (n = 11). No significant difference was observed
between hypersensitivity pneumonitis patients (H P) (n = 7) and
normals. Columns represent means and bars standard deviations.
• p < 0.05 when compared to norma Is . .& p < 0.05 when compared
to non-active sa rcoidosis patients.
SA
SNA
HP
Fig. 1. cr. 1 M RCE in BAL rrom (left to ri_g_ht) normals (0 ).
active sarcoidosis patients (0 ), inuctiv~ surco1dosis patients (i:l)
and hypersensitivity pneumonitis patients (S). Columns and bars
represent respectively me;1ns and standard dcviatjons. Sigoilicant
dini:rcnces ure observed between SA and N , between SNA and N.
between llP a nd Nand between SA and SNA. Same symbols (• •.& )
as in ligur.:! I. •• p < O.OI when compa red t l) nonnals.
Immunog/obulins G and M and a 2 -macroglobulin in
BAL
A significant increase in RCE of o: 2 M (fig. 2) and
IgG (table JI) is observed· in the active sarcoidosis
501
ANTIPROTEASES IN BRONCHOALVEOLAR LAVAGE
group (mean values respectively 0.39 and 1.90)
compared to nonnals (respectively 0.05 and 0.74)
(p<O.Ol). RCE of IgM for the active sarcoidosis
patients (mean= 0.51) was also higher than that of the
normals group (mean= 0.08) (p > 0.05). Patients with
hypersensitivity pneumonitis also demonstrated a
significant increase in RCE of a 2 M (0.69), IgG (2.28)
as well as I gM ( 1.54) compared to the normal group
(fig. 2, table II).
•(4.1)
~
•
••
•
3
rx 1-protease inhibitor levels in BAL
The RCE mean value of a 1 PI in BAL from the
normal group was 1.24, significantly lower than the
corresponding RCE value in the active sarcoidosis
group (2.04) (p < 0.0 I) or the hypersensitivity pneumonitis group (l .83) (p < 0.05). The mean RCE value
in the non-active sarcoidosis group ( 1.08) was not
significantly different from the normal value (fig. 3).
In the hypersensitivity pneumonitis group and in
the inactive sarcoidosis groups, a significant correlation between a 1PI RCE and a 2 M RCE is observed
(respectively r = 0.86 and r=0.57, p<0.05). In the
active sarcoidosis group, there is no significant
correlation between the two antiproteases RCE
(r = 0.34). However, in the group of 17 patients with
radiographic stage I and II disease, a significant
correlation is again demonstrated (r = 0.67, p < 0.05).
In contrast, no correlation between a 1 PI RCE and
a 2 M RCE is observed in the normal group. No other
correlation between protein and cellular data of the
BAL was significant in the patient groups.
2
•
•
..••
•
•
•
•
•
I
•
•
•
Follow-up studies
In the group of 12 patients with sarcoidosis, who
were lavaged at least twice, eight were considered
initially as 'active' and remained untreated. These
patients, except one, had initially high a 2 M RCE and
BAL T 4 /T 8 ratios (table Ill). In subsequent lavages,
both a 2 M RCE values and BAL T 4 /T 8 values
remained above the mean range of the corresponding
normal values except for one patient who initially
suffered stage I disease with erythema nodosum and
after eight months was considered free of disease.
Two other patients had initially 'active' disease and
high a 2 M RCE; their a 2 M RCE dropped to the
normal range under treatment (fig. 4).
•
•
0
N
SA
SNA
Fig. 3. RCE value of o:,PI in BAL from patients with active
sarcoidosis (ID ) or with hypersensitivity pneumonitis (ill) is
increased when compared to normals (D ) or to patients with
inactive sarcoidosis (El). Same symbols (• and A) as figure I.
Finally, two patients were under steroid treatment
before being referred to us. Parallel to the progressive
withdrawal of the steroids, we observed a gradual
Table 3. - BAL data from sequentiallavages in "active" untreated sarcoidosis patients
Total cell count
x 106 cells/lOO ml
Initial BAL
n=8
Second BAL after 3-4 months
n=8
Third BAL after 6-9 months
n=4
~ mean
Lymphocytes
%
T/f8
ex 2MRCE
36.5 ~
27.4
9.7
0.37
32.4
28.2
13.8
0.45
26.3
14.7
10.6
0.32
values; RCE:relative coefficient of excretion.
HP
502
Y. SIBILLE ET AL .
6.0
LU
5.0
0
a:
4.0
<g, 3.0
-
2.0
r.r~~~~~~~~~TT~~~~~
1.0
LU
0
a:
~ 0.2
.Ql 0.1
6
12
Months
18
Fig. 5. Cellular (T4 {f8 ratio) and protein (IgG, lgM and a 2 M
RCE) parameters in BAL from two patients treated with steroids at
the time of diagnosis in which the corticotherapy was discontinued,
immediately for (0 ---0 ) and 6 months later for ( e--e) and
these parameters were further followed 6, 12 and 18 months later.
I
6
12
18
Months
Fig. 4. Cellular (T4 /T 8 ratio) and protein (IgG, !gM and a 2 M
expressed in RCE) parameters in BAL from two patients with
active sarcoidosis at the lime of diagnosis (before steroid treatment)
and 6. 12 and 18 months after the beginning ofcorticotherapy (32
mg Methylprednisolone daily). Dashed zones represent no rmal
ranges (mean± I sta ndard deviation).
increase of the a 2 M RCE value prior to BAL T 4 /T 8
changes (fig. 5).
Discussion
Much promise has been expected from the development of the BAL. For example, BAL lymphocytosis
or BAL lymphocyte subpopulation studies were
proposed as sensitive markers of sarcoidosis alveolitis
[6, 8, 10]. Since previous reports suggested that a high
lymphocytosis in the BAL reflects a 'high intensity
alveolitis', we arbitrarily divided our patients with
sarcoidosis into two groups ('active' and 'inactive')
using 15% lymphocytes in the total BA L cell
population as the discriminating criterion (7]. However, this criterion is not uniformly accepted and more
sensitive criteria may be required (18, 19]. The study
of lymphocyte subpopulations has been proposed by
different groups to better assess the alveolitis in
sarcoidosis [10, 20, 21] . As reported by others, we
observed in the present study a significant increase of
the BAL T 4{f8 ratio in the active sarcoidosis group,
without any significant change in the blood T
lymphocyte subpopulations when compared to the
normal and non-active sarcoidosis groups [I 0, 22].
No significant change is noticed in the blood or in the
BAL lymphocyte subpopulations from patients with
inactive sarcoidosis. Different groups reported an
increased proportion of OKT8 (suppressor) lymphocytes in BAL from hypersensitivity pneumonitis
patients [23- 25]. We observed that the mean value of
the BAL T 4 /T 8 in the hypersensitivity group was not
significantly different from the normal group. This
observation may be related to the delay between the
last exposure to the allergen and the lavage procedure
as previously reported [26], more than to methodological problems. Patients with active pulmonary
sarcoidosis have a higher RCE for a 2 M with little
overlap with the normal group values. The group of
patients with sarcoidosis considered as inactive (based
on BAL lymphocytosis) expressed a significantly
higher mean value of RCE for a 2 M when compared
to the normal group. H owever, ten out of the eleven
patients in this group have a RCE for a 2 M within the
normal range and no symptoms; the cx 2 M RCE of
0.78 was observed in a patient with 7% lymphocytes
in the BAL. However, the patient was symptomatic
(fatigue and dyspnoea) and had a dramatic increase in
BAL T 4 /T 8 ratio of 9.3. This supports further the
ANTIPRO T EASES fN BRONCHOA L VEOLAR LAVAGE
concept that the BAL T 4 /T 8 ratio provides a more
sensitive cellular marker of the alveolitis than the
BAL total lymphocytosis.
Although the follow-up studies concerned a limited
number of patients over a limited period of time, we
observed that patients with active disease kept <X 2 M
RCE values above the normal range when untreated,
whi le the values dropped to the normal range under
steroid treatment. Patients with normal <X 2 M RCE
under steroids demonstrated a rise of <X 2 M RCE back
to abnormal values when steroid treatment was
discontinued. Furthermore, in these patients, it
appears that <X 2 M RCE changes occur prior to both
the BAL lymphocytosis and T 4 /T 8 ratio suggesting
that <X2 M better reflects early changes of the intensity
of the alveolitis. As described for <X2 M, the levels of
the major antiprotease (<X 1PI) were significantly
increased in BAL from patients with active pulmonary sarcoidosis or hypersensitivity pneumonitis.
Moreover, in the hypersensitivity pneumonitis and
inactive sarcoidosis groups (but not in normal
volunteers) we observed a linear correlation between
the concentrations of these antiproteases after correction of the values for their serum concentration and
dilution of the BAL. This occurred despite the large
difference in their molecular weight (53 .000 for <X 1 PI
and 820.000 for <X2 M). This correlation was also
present in the 17 patients of the active sarcoidosis
group with stage I and stage II disease. Whether the
remaining 7 patients (stage III) with high <X 2 M RCE
associated with relatively low <X 1 PI RCE represent a
subgroup of patients, or have a different prognosis,
remains unknown at this point.
Although our method of immunoassay does not
allow us to distinguish between native and complexed
antiproteases, or to estimate the antiprotease activity,
it still demonstrates a local increase of the two major
antiprotease levels in diseases where proteolytic
activity is likely to be enhanced.
In conclusion, the measurement of soluble components in BAL in addition to cellular studies may help
the clinician in the management of patients with
interstitial lung disease. Moreover, three lines of
evidence suggest that <X2 M may be a better index of
the a lveolitis than the BAL lymphocytosis or T 4 /T 8
ratio: a) the overlap of BAL T 4 /T 8 ratios between
normals and patients with active sarcoidosis is larger
than the overlap of <X 2 M RCE values; b) in sarcoidosis, the changes of <X 2 M occur earlier than the
changes of BAL T 4 /T 8 ratios during the course of
the disease; c) the RCE of 11 2 M is elevated in the
acute phase of hypersensitivity pneumonitis while the
T 4 /T 8 ratios remain normal or decreased. Finally,
the correlated increase of the two major antiproteases (<X1 PI and 112 M) in BAL from patients with
interstitial lung disease may be at least part of the
defence mechanism against the potential proteolytic
activity responsible for the fibrosis occurring in
advanced sarcoidosis or hypersensitivity pneumonitis. However definitive analysis of these data awaits
long term studies.
503
Acknowledgements: The authors wish to thank J.P.
Dehennin and C. Desaeger for thei r excellent
technical help, and Drs. Y. Coyette, J.L. Doyen, P.
Minette, P. Lemaire and P. Scory who performed
some of the bronchoalveolar lavages, Drs. M.
Buysschaert, P. Dubois, W. Esselinckx, J. Prignot
and J. Steyaert who referred their patients to the
study and J.P. Delwiche for statistical help. They also
acknowledge the excellent editorial help of M.P.
Heylens and the graphical work of C. Deneffe.
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of disease. Chest, 1984,85, 514-518.
RESUME: 11 s'agit d'une evaluation de differents composants
cellulaires et solubles du lavage broncho-alveolaire de patients
atteints d'une maladie interstitielle pulmonaire. Nous observons
une augmentation du rapport des lymphocytes T JT8 dans le lavage
broncho-alveolaire, et non dans le sang, chez 24 patients atteints
d' une sarcoldose pulmonaire active, par comparaison avec 16
individus normaux, et avec I I patients avec une sarcoldose
pulmonaire inactive. Sept patients atteints de pneumopathie
d'hypersensibilite, ont un rapport T 4 /T8 normal. Dans la sarco·idose active et dans le groupe de pneumopathie d'hypersensibilite,
!'alpha I anti protease (alpha I PI) du lavage broncho·alveolaire est
significativement plus marquee que dans le groupe normal. et l'on
observe une correlation significative entre les deux anti-proteases
(alpha 2-macroglobuline et alpha I PI). Ces donnces dernontrent
que les niveaux d'anti-protcases (alpha I PI et alpha 2 M) sont
augmentes dans le tractus respiratoire inferieur des patients avec
maladie pulmonaire interstitielle et que, parmi les composants
cellulaires et solubles du lavage broncho-alveolaire, !'alpha 2macroglobuline est un marqueur sensible de l'alveolite.